The 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor lovastatin reduces severity of L-DOPA-induced abnormal involuntary movements in experimental Parkinson's disease

J Neurosci. 2008 Apr 23;28(17):4311-6. doi: 10.1523/JNEUROSCI.4720-07.2008.

Abstract

Chronic L-3,4-dihydroxyphenylalanine (L-DOPA) treatment of Parkinson's disease (PD) often leads to debilitating involuntary movements, termed L-DOPA-induced dyskinesia (LID), about which the rodent analog, the abnormal involuntary movements (AIMs), has been associated consistently with an activation of the Ras-extracellular signal-regulated kinase 1/2 (ERK1/2) mitogen-activated protein kinase signaling pathway. Previous studies have shown that lovastatin, a specific inhibitor of the rate-limiting enzyme in cholesterol biosynthesis, can also inhibit Ras isoprenylation and activity and subsequently the phosphorylation of ERK1/2 (pERK1/2). We hypothesized that lovastatin treatment-commenced previous L-DOPA exposure could reduce AIM incidence and severity in the 6-hydroxydopamine (6-OHDA) rat model of PD by secondarily preventing the L-DOPA/Benserazide-induced increase in pERK1 levels. The lovastatin-L-DOPA/Benserazide-treated 6-OHDA animals displayed less severe rotational behavior as well as a dramatic reduction in AIM severity than the L-DOPA/Benserazide-treated ones. Such lower AIM severity was associated with a decrease in L-DOPA-induced increase in the following: (1) striatal pERK1 and (2) DeltaFosB levels, and (3) theta/alpha oscillations of substantia nigra pas reticulata (SNr) neurons as well as (4) a normalization of SNr firing frequency. Those results strongly suggest that lovastatin might represent a treatment option for managing LID in PD.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Dyskinesias / drug therapy*
  • Dyskinesias / enzymology
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use*
  • Levodopa / toxicity*
  • Lovastatin / therapeutic use*
  • Male
  • Parkinson Disease, Secondary / chemically induced
  • Parkinson Disease, Secondary / drug therapy*
  • Parkinson Disease, Secondary / enzymology
  • Rats
  • Rats, Wistar
  • Severity of Illness Index*

Substances

  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Levodopa
  • Lovastatin